Abstract 3600: DCC-3116, a first-in-class selective inhibitor of ULK1/2 kinases and autophagy, synergizes with the KRASG12C inhibitor sotorasib resulting in tumor regression in KRAS mutant NSCLC xenograft models
Authors: Martin McMahon, Madhumita Bogdan, Mary J. Timson, Hikmat Al-Hashimi, Phaedra Ghazi, Yu Zhan, Bryan D. Smith, Conan G. Kinsey, Daniel L. Flynn
Journal: Cancer Research (2022)

Abstract Mutationally-activated RAS oncoproteins are detected in approximately 19% of newly diagnosed human cancers and have been targets for drug discovery for over 40 years. Recently, the FDA approved sotorasib, a covalent inhibitor of KRASG12C, for the treatment of non-small cell lung cancer (NSCLC). Although sotorasib demonstrated clear clinical benefits, the emergence of drug resistance has led to drug combination approaches with the goal of deepening and sustaining the durability of patient responses. One potential mechanism of drug resistance is the induction of autophagy, which cancer cells use to survive during periods of stress such as treatment with pathway-targeted therapies. Indeed, KRAS-mutated cancer cells have been shown to exhibit constitutive autophagy for survival. Additionally, such cells further increase autophagy when treated with pathway-targeted inhibitors of RAS&amp;gt;RAF&amp;gt;MEK&amp;gt;ERK MAP kinase signaling as a resistance mechanism. Hence, the combination of a KRASG12C inhibitor with a specific and potent autophagy inhibitor could lead to deeper and more sustained clinical responses. DCC-3116 is an investigational, potent and selective pharmacological inhibitor of the protein kinases ULK1 and ULK2, which are critical initiating components of the autophagy pathway. Treatment of KRASG12C non-small cell lung cancer (NSCLC) cell lines with sotorasib induced autophagy by ~2-fold via activation of ULK kinases as measured by an increase in ULK-mediated phosphorylation of ATG13. Sotorasib-mediated ULK kinase activation, and resulting autophagic flux, was inhibited by DCC-3116 in a dose-dependent manner with IC50 values of 81-160 nM in NSCLC cell lines. These effects translated to in vivo efficacy. In the Calu-1 and H358 KRASG12C NSCLC xenograft models, the combination of DCC-3116 and sotorasib resulted in tumor regression whereas single treatment arms afforded only inhibition of tumor growth. A NSCLC KRASG12C patient derived xenograft (PDX) model further supported the DCC-3116 and sotorasib combination with increased tumor growth inhibition compared to sotorasib alone. These data demonstrate a compelling rationale to study DCC-3116 in combination with KRASG12C inhibitors such as sotorasib in NSCLC patients. DCC-3116 is currently in a Phase 1 clinical trial in patients with advanced solid tumors with documented KRAS, NRAS or BRAF mutations (NCT04892017). Citation Format: Martin McMahon, Madhumita Bogdan, Mary J. Timson, Hikmat Al-Hashimi, Phaedra Ghazi, Yu Zhan, Bryan D. Smith, Conan G. Kinsey, Daniel L. Flynn. DCC-3116, a first-in-class selective inhibitor of ULK1/2 kinases and autophagy, synergizes with the KRASG12C inhibitor sotorasib resulting in tumor regression in KRAS mutant NSCLC xenograft models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3600.